We propose to rationally design and produce protein fold switches through a method we call sequence transplantation. This method involves substituting the amino acid sequence encoding a substructure from a large protein with a sequence hybrid. The hybrid will be a carefully designed mixture of the subsequence and another sequence of equivalent length that encodes a structurally dissimilar domain, predisposing the hybrid toward both parent folds. We hypothesize that as an isolated polypeptide chain, the hybrid would fold into the structure of the domain, but when transplanted into the large protein, it would adopt the structure native to its parent subsequence. Results from a recent computational study suggest that a similar phenomenon might occur in nature through alternative gene splicing. If so, engineering and biophysically characterizing such constructs in the lab would provide deep insights into this currently arcane natural process. Accordingly, we have developed a rational procedure for converting a pair of distinctly folded proteins with low sequence identity into protein fold switches. This step-by-step method will provide insight into fundamental design principles, informing our designs as we go and improving computational methods for protein structure prediction and protein design. Folded designs with sequence identity ? 50% will be structurally and energetically characterized using NMR spectroscopy and denaturation/renaturation experiments, respectively. We expect that investigating these characteristics will provide fundamental insight into the relationship between sequence, structure, and energetics. Identifying the different conformations accessible to a given polypeptide chain will provide insight into medically relevant cases of structural promiscuity. These include intrinsically disordered proteins and misfolding diseases. If successful, this approach suggests a modular mechanism for protein evolution in which small, marginally stable proteins can combine to form larger alternative folds, offering a new perspective to genomic and proteomic studies.